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INTRODUCTION: Lung cancer in never-smoker (LCINS) patients accounts for 20% of lung cancer cases, and its biology remains poorly understood, particularly in genetically admixed populations. We elucidated the molecular profile of driver genes in Brazilian LCINS. METHODS: The mutational and gene fusion status of 119 lung adenocarcinomas from self-reported never-smoker patients, was assessed using targeted sequencing (NGS), nCounter, and immunohistochemistry. A panel of 46 ancestry-informative markers determined patients' genetic ancestry. RESULTS: The most frequently mutated gene was EGFR (49.6%), followed by TP53 (39.5%), ALK (12.6%), ERBB2 (7.6%), KRAS (5.9%), PIK3CA (1.7%), and less than 1% alterations in RET, NTRK1, MET∆ex14, PDGFRA, and BRAF. Except for TP53 and PIK3CA, all other alterations were mutually exclusive. Genetic ancestry analysis revealed a predominance of European (71.1%), and a higher African ancestry was associated with TP53 mutations. CONCLUSION: Brazilian LCINS exhibited a similar molecular profile to other populations, except the increased ALK and TP53 alterations. Importantly, 73% of these patients have actionable alterations that are suitable for targeted treatments.
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Glioblastoma is the most frequent primary malignant brain tumor without effective treatment, which makes this work extremely relevant. The study of the bioactive compounds from medicinal plants plays an important role in the discovery of new drugs.This research investigated the constituents of Tapirira guianensis and its antitumor potential (in vitro and in vivo) in glioblastoma. The T. guianensis extracts were characterized by mass spectrometry. The ethyl acetate partition (01ID) and its fractions 01ID-F2 and 01ID-F4 from T. guianensis showed potential antitumor treatment evidenced by selective cytotoxicity for GAMG with IC50 14.1 µg/mL, 83.07 µg/mL, 59.27 µg/mL and U251 with IC50 25.92 µg/mL, 37.3 µg/mL and 18.84 µg/mL. Fractions 01ID-F2 and 01ID-F4 were 10 times more selective when compared to TMZ and 01ID for the two evaluated cell lines. T. guianensis also reduced matrix metalloproteinases 2â-â01ID-F2 (21.84%), 01ID-F4 (29.6%) and 9â-â01ID-F4 (73.42%), ID-F4 (53.84%) activities, and induced apoptosis mainly through the extrinsic pathway. Furthermore, all treatments significantly reduced tumor size (01ID p < 0,01, 01ID-F2 p < 0,01 and 01ID-F4 p < 0,0001) and caused blood vessels to shrink in vivo. The present findings highlight that T. guianensis exhibits considerable antitumor potential in preclinical studies of glioblastoma. This ability may be related to the phenolic compounds and sesquiterpene derivatives identified in the extracts. This study deserves further in vivo research, followed by clinical investigation.
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Antineoplásicos , Glioblastoma , Plantas Medicinales , Glioblastoma/tratamiento farmacológico , Extractos Vegetales/química , Angiogénesis , Plantas Medicinales/química , Antineoplásicos/farmacología , Apoptosis , Línea Celular TumoralRESUMEN
BACKGROUND: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features. METHODS: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. RESULTS: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). CONCLUSION: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.
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Antígeno B7-H1 , Inestabilidad de Microsatélites , Neoplasias Primarias Desconocidas , Humanos , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/patología , Antígeno B7-H1/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Pronóstico , Microambiente Tumoral , InmunohistoquímicaRESUMEN
Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, known for its heterogeneity and treatment-associated toxicity, and there is a critical need for new therapeutic targets. We analyzed the somatic mutation profile of 15 driver genes in 69 Latin-Iberian molecularly characterized medulloblastomas using the Illumina TruSight Tumor 15 panel. We classified the variants based on their clinical impact and oncogenicity. Among the patients, 66.7% were MBSHH, 13.0% MBWNT, 7.3% MBGrp3, and 13.0% MBGrp4. Among the 63 variants found, 54% were classified as Tier I/II and 31.7% as oncogenic/likely oncogenic. We observed 33.3% of cases harboring at least one mutation. TP53 (23.2%, 16/69) was the most mutated gene, followed by PIK3CA (5.8%, 4/69), KIT (4.3%, 3/69), PDGFRA (2.9%, 2/69), EGFR (1.4%, 1/69), ERBB2 (1.4%, 1/69), and NRAS (1.4%, 1/69). Approximately 41% of MBSHH tumors exhibited mutations, TP53 (32.6%) being the most frequently mutated gene. Tier I/II and oncogenic/likely oncogenic TP53 variants were associated with relapse, progression, and lower survival rates. Potentially actionable variants in the PIK3CA and KIT genes were identified. Latin-Iberian medulloblastomas, particularly the MBSHH, exhibit higher mutation frequencies than other populations. We corroborate the TP53 mutation status as an important prognostic factor, while PIK3CA and KIT are potential therapeutic targets.
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BACKGROUND: Gastrointestinal stromal tumors (GIST) represent a significant clinical challenge due to their metastatic potential and limited treatment options. Raf kinase inhibitor protein (RKIP), a suppressor of the MAPK signaling pathway, is downregulated in various cancers and acts as a metastasis suppressor. Our previous studies demonstrated low RKIP expression in GIST and its association with poor outcomes. This study aimed to expand on the previous findings and investigate the biological and therapeutic implications of RKIP loss on GIST. METHODS: To validate the RKIP prognostic significance, its expression was evaluated by immunohistochemistry in 142 bona fide GIST cases. The functional role of RKIP was evaluated in vitro, using the GIST-T1 cell line, which was knocked out for RKIP. The biological and therapeutic implications of RKIP were evaluated by invasion, migration, apoptosis, and 2D / 3D viability assays. Additionally, the transcriptome and proteome of RKIP knockout cells were determined by NanoString and mass spectrometry, respectively. RESULTS: Immunohistochemical analysis revealed the absence of RKIP in 25.3% of GIST cases, correlating with a tendency toward poor prognosis. Functional assays demonstrated that RKIP knockout increased GIST cells' invasion and migration potential by nearly 60%. Moreover, we found that RKIP knockout cells exhibited reduced responsiveness to Imatinib treatment and higher cellular viability in 2D and 3D in vitro models, as assessed by apoptosis-related protein expression. Through comprehensive genetic and proteomic profiling of RKIP knockout cells, we identified several putative RKIP-regulated proteins in GIST, such as COL3A1. CONCLUSIONS: Using a multidimensional integrative analysis, we identified, for the first time in GIST, molecules and pathways modulated by RKIP that may potentially drive metastasis and, consequently, poor prognosis in this disease.
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INTRODUCTION: TP53 is the most frequently mutated gene in lung tumors, but its prognostic role in admixed populations, such as Brazilians, remains unclear. In this study, we aimed to evaluate the frequency and clinicopathological impact of TP53 mutations in non-small cell lung cancer (NSCLC) patients in Brazil. METHODS: We analyzed 446 NSCLC patients from Barretos Cancer Hospital. TP53 mutational status was evaluated through targeted next-generation sequencing (NGS) and the variants were biologically classified as disruptive/nondisruptive and as truncating/nontruncating. We also assessed genetic ancestry using 46 ancestry-informative markers. Analysis of lung adenocarcinomas from the cBioportal dataset was performed. We further examined associations of TP53 mutations with patients' clinicopathological features. RESULTS: TP53 mutations were detected in 64.3% (n = 287/446) of NSCLC cases, with a prevalence of 60.4% (n = 221/366) in lung adenocarcinomas. TP53 mutations were associated with brain metastasis at diagnosis, tobacco consumption, and higher African ancestry. Disruptive and truncating mutations were associated with a younger age at diagnosis. Additionally, cBioportal dataset revealed that TP53 mutations were associated with younger age and Black skin color. Patients harboring disruptive/truncating TP53 mutations had worse overall survival than nondisruptive/nontruncating and wild-type patients. CONCLUSION: TP53 mutations are common in Brazilian lung adenocarcinomas, and their biological characterization as disruptive and truncating mutations is associated with African ancestry and shorter overall survival.
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Adenocarcinoma del Pulmón , Población Negra , Neoplasias Pulmonares , Proteína p53 Supresora de Tumor , Humanos , Adenocarcinoma del Pulmón/etnología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Población Negra/genética , Brasil/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/etnología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/etnología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Mutación , Prevalencia , Pronóstico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Lung cancer is the deadliest cancer worldwide. Tissue biopsy is currently employed for the diagnosis and molecular stratification of lung cancer. Liquid biopsy is a minimally invasive approach to determine biomarkers from body fluids, such as blood, urine, sputum, and saliva. Tumor cells release cfDNA, ctDNA, exosomes, miRNAs, circRNAs, CTCs, and DNA methylated fragments, among others, which can be successfully used as biomarkers for diagnosis, prognosis, and prediction of treatment response. Predictive biomarkers are well-established for managing lung cancer, and liquid biopsy options have emerged in the last few years. Currently, detecting EGFR p.(Tyr790Met) mutation in plasma samples from lung cancer patients has been used for predicting response and monitoring tyrosine kinase inhibitors (TKi)-treated patients with lung cancer. In addition, many efforts continue to bring more sensitive technologies to improve the detection of clinically relevant biomarkers for lung cancer. Moreover, liquid biopsy can dramatically decrease the turnaround time for laboratory reports, accelerating the beginning of treatment and improving the overall survival of lung cancer patients. Herein, we summarized all available and emerging approaches of liquid biopsy-techniques, molecules, and sample type-for lung cancer.
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Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Detección Precoz del Cáncer , Biomarcadores de Tumor/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Biopsia Líquida/métodosRESUMEN
Lung cancer has the highest mortality rate among all cancer types, resulting in over 1.8 million deaths annually. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of non-small cell lung cancer (NSCLC). ICIs, predominantly monoclonal antibodies, modulate co-stimulatory and co-inhibitory signals crucial for maintaining immune tolerance. Despite significant therapeutic advancements in NSCLC, patients still face challenges such as disease progression, recurrence, and high mortality rates. Therefore, there is a need for predictive biomarkers that can guide lung cancer treatment strategies. Currently, programmed death-ligand 1 (PD-L1) expression is the only established biomarker for predicting ICI response. However, its accuracy and robustness are not consistently reliable. This review provides an overview of potential biomarkers currently under development or in the validation stage that hold promise in improving the classification of responders and non-responders to ICI therapy in the near future.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1 , Biomarcadores , Inmunoterapia/métodos , Antígeno B7-H1 , Biomarcadores de Tumor/metabolismoRESUMEN
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Leucocitos Mononucleares/patología , Biomarcadores , Inmunoglobulina M , AutofagiaRESUMEN
Glioblastoma (GBM) is an incurable primary brain tumor with a poor prognosis. Resection, radiation therapy, and temozolomide (TMZ) are insufficient to increase survival, making the treatment limited. Thus, the search for more effective and specific treatments is essential, making plants a promising source for elucidating new anti-glioblastoma compounds. Accordingly, this study investigated the effects of four fractions of hexane and ethyl acetate extract of Annona coriacea Mart., enriched with acetogenins, against GBM cell lines. All four fractions were selectively cytotoxic to GBM cells when compared to TMZ. Moreover, A. coriacea fractions delayed cell migration; reduced cytoplasmic projections, the metalloproteinase 2 (MMP-2) activity; and induced morphological changes characteristic of necroptosis, possibly correlated with the increase in receptor-interacting protein kinase 1 and 3 (RIP-1 and RIP-3), apoptosis-inducing factor (AIF), and the non-activation of cleaved caspase 8. The present findings reinforce that fractions of A. coriacea Mart. should be considered for more studies focusing treatment of GBM.
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Annona , Neoplasias Encefálicas , Glioblastoma , Humanos , Metaloproteinasa 2 de la Matriz , Acetogeninas/farmacología , Necroptosis , Glioblastoma/metabolismo , Temozolomida/farmacología , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos , ApoptosisRESUMEN
BACKGROUND: Targeted and immunotherapies are currently moving toward early-stage settings for patients with non-small cell lung cancer (NSCLC). Predictive biomarkers data are scarce in this scenario. We aimed to describe the frequency of EGFR mutations and PD-L1 expression levels in early-stage non-squamous patients with NSCLC from a large, single Brazilian oncology center. METHODS: We retrospectively evaluated patients with NSCLC diagnosed at an early-stage (IB to IIIA-AJCC seventh edition) at Barretos Cancer Hospital (n = 302). EGFR mutational status was assessed in FFPE tumor tissues using distinct methodologies (NGS, Cobas, or Sanger sequencing). PD-L1 expression was evaluated by immunohistochemistry (clone 22C3) and reported as Tumor Proportion Score (TPS), categorized as <1%, 1-49%, and ≥50%. We evaluated the association between EGFR mutational status and PD-L1 expression with sociodemographic and clinicopathological parameters by Fisher's test, qui-square test, and logistic regression. Survival analysis was assessed by the Kaplan-Meier method and Cox regression model. RESULTS: EGFR mutations were detected in 17.3% (n = 48) of cases and were associated with female sex, never smokers, and longer overall and event-free survival. PD-L1 positivity was observed in 36.7% (n = 69) of cases [TPS 1-49% n = 44(23.4%); TPS ≥50% n = 25(13.3%)]. PD-L1 positivity was associated with smoking, weight loss, and higher disease stages (IIB/IIIA). CONCLUSION: The frequencies of EGFR mutations and PD-L1 positivity were described for early-stage non-squamous patients with NSCLC. These results will be essential for guiding treatment strategies with the recent approvals of osimertinib and immunotherapy in the adjuvant setting.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Femenino , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Brasil/epidemiología , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Mutación , Receptores ErbB/genéticaRESUMEN
PURPOSE: Medulloblastoma is the most frequent pediatric malignant brain tumor, and is divided into four main subgroups: WNT, SHH, group 3, and group 4. MYCN amplification is an important medulloblastoma prognostic biomarker. We aimed to molecular classify and predict MYCN amplification in a single assay. METHODS: It was included 209 medulloblastomas from 205 patients (Brazil, Argentina, and Portugal), divided into training (n = 50) and validation (n = 159) sets. A nCounter assay was carried out using a custom panel for molecular classification, with additional genes, including MYCN. nSolver 4.0 software and the R environment were used for profiling and MYCN mRNA analysis. MYCN amplification by FISH was performed in 64 cases. RESULTS: The 205 medulloblastomas were classified in SHH (44.9%), WNT (15.6%), group 3 (18.1%) and group 4 (21.4%). In the training set, MYCN amplification was detected in three SHH medulloblastomas by FISH, which showed significantly higher MYCN mRNA counts than non-FISH amplified cases, and a cutoff for MYCN amplification was established ([Formula: see text] + 4σ = 11,124.3). Applying this threshold value in the validation set, we identified MYCN mRNA counts above the cutoff in three cases, which were FISH validated. CONCLUSION: We successfully stratified medulloblastoma molecular subgroups and predicted MYCN amplification using a single nCounter assay without the requirement of additional biological tissue, costs, or bench time.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Brasil , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Niño , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Proteína Proto-Oncogénica N-Myc/genéticaRESUMEN
INTRODUCTION: Lung cancer is the deadliest cancer worldwide and in Brazil. Despite strong evidence, lung cancer screening by low-dose computed tomography (LDCT) in high-risk individuals is far from a reality in many countries, particularly in Brazil. Brazil has a universal public health system marked with important inequalities. One affordable strategy to increase the coverage of resources is to use mobile units. OBJECTIVES: To describe the implementation and results of an innovative lung cancer prevention program that integrates tobacco cessation and lung cancer screening using a mobile CT unit. METHODOLOGY: From May 2019 to Dec 2020, health professionals from 18 public primary health care units in Barretos, Brazil, were trained to offer smoking cessation counseling and treatment. Eligible high-risk participants of this program were also invited to perform lung cancer screening in a mobile LDCT unit that was specially conceived to be dispatched to the community. A detailed epidemiological questionnaire was administered to the LDCT participants. RESULTS: Among the 233 screened participants, the majority were women (54.9%), and the average age was 62 years old. A total of 52.8% of participants showed high or very high nicotine dependence. After 1 year, 27.8% of participants who were involved in smoking cessation groups had quit smoking. The first LDCT round revealed that the majority of participants (83.7%) exhibited lung-Rads 1 or 2; 7.3% exhibited lung-Rads 3; 7.7% exhibited lung-Rads 4a; and 3% exhibited lung-Rads 4b or 4x. The three participants with lung-Rads 4b were further confirmed, and their surgery led to the diagnosis of early-stage cancer (1 case of adenocarcinoma and two cases of squamous cell carcinoma), leading to a cancer diagnosis rate of 12.8/1000. CONCLUSION: Our results indicate promising outcomes for an onsite integrative program enrolling high-risk individuals in a middle-income country. Evidence barriers and challenges remain to be overcome.
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Neoplasias Pulmonares , Tomografía Computarizada por Rayos X , Brasil/epidemiología , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/epidemiología , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodosRESUMEN
Herein, we present a rare case of a nine-month-old boy diagnosed with infant-type hemispheric glioma (gliosarcoma subtype) at the left frontal lobe. Following subtotal resection, the patient started chemotherapy with the BABY POG protocol. We describe the clinical diagnosis, histological characteristics, radiological features, molecular aspects, and management of this tumor. A comprehensive molecular analysis on the tumor tissue showed a TPR-NTRK1 gene fusion. The patient was treated with a TRK inhibitor, larotrectinib, and exhibited a stable disease with residual lesion following 8 months of target therapy. The present study is the first report of an infantile gliosarcoma harboring NTRK1 rearrangement treated with larotrectinib.
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Astrocitoma , Glioma , Gliosarcoma , Glioma/tratamiento farmacológico , Glioma/genética , Gliosarcoma/tratamiento farmacológico , Humanos , Lactante , Masculino , Pirazoles/uso terapéutico , Pirimidinas , Receptor trkA/genéticaRESUMEN
BACKGROUND: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC). OBJECTIVE: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals. METHODS: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology. RESULTS: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics. CONCLUSION: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
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Alphapapillomavirus , Carcinoma de Células Escamosas , Acalasia del Esófago , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Infecciones por Papillomavirus , Brasil , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiología , ADN Viral/genética , Acalasia del Esófago/diagnóstico , Acalasia del Esófago/epidemiología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiología , Humanos , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Microsatellite instability (MSI) in non-small cell lung cancer (NSCLC) is uncommon; however, most studies refer to European and Asian populations. There are currently no data on MSI frequency in highly admixed populations, such as the one represented by Brazilian NSCLC patients. AIM: This study aimed to evaluate the frequency of MSI in Brazilian NSCLC patients. METHODS: We evaluated 526 patients diagnosed with NSCLC at the Barretos Cancer Hospital (Brazil). The molecular MSI evaluation was performed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. The mutation profile of MSI-positive cases was performed using next-generation sequencing. RESULTS: Only 1 patient was MSI positive (0.19%). This patient was a female, white, and active smoker, and she was diagnosed with clinical stage IV lung adenocarcinoma at 75 years old. The molecular profile exhibited 4 Tumor Protein p53 (TP53) mutations and the absence of actionable mutations in the Epidermal Growth Factor Receptor (EGFR), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), or V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) genes. CONCLUSIONS: The frequency of MSI in Brazilian NSCLC patients is equally rare, a finding that is consistent with the current literature based on other populations such as Europeans, North Americans, and Asians.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Colorrectales , Neoplasias Pulmonares , Animales , Brasil , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Colorrectales/patología , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Inestabilidad de Microsatélites , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: Pilocytic astrocytoma is the most frequent pediatric glioma. Despite its overall good prognosis, complete surgical resection is sometimes unfeasible, especially for patients with deep-seated tumors. For these patients, the identification of targetable genetic alterations such as NTRK fusions, raised as a new hope for therapy. The presence of gene fusions involving NTRK2 has been rarely reported in pilocytic astrocytoma. The aim of the present study was to investigate the frequency of NTRK2 alterations in a series of Brazilian pilocytic astrocytomas. METHODS: Sixty-nine pilocytic astrocytomas, previously characterized for BRAF and FGFR1 alterations were evaluated. The analysis of NTRK2 alterations was performed using a dual color break apart fluorescence in situ hybridization (FISH) assay. RESULTS: NTRK2 fusions were successfully evaluated by FISH in 62 of the 69 cases. Neither evidence of NTRK2 gene rearrangements nor NTRK2 copy number alterations were found. CONCLUSIONS: NTRK2 alterations are uncommon genetic events in pilocytic astrocytomas, regardless of patients' clinicopathological and molecular features.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Astrocitoma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Fusión Génica , Glioma/genética , Humanos , Hibridación Fluorescente in Situ , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
INTRODUCTION AND OBJECTIVES: PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. METHODS: We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. RESULTS: A total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. CONCLUSION: Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.
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Aciltransferasas , Enfermedad del Hígado Graso no Alcohólico , Fosfolipasas A2 Calcio-Independiente , Adulto , Humanos , Alelos , Predisposición Genética a la Enfermedad , Genotipo , Hígado/patología , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/etnología , Enfermedad del Hígado Graso no Alcohólico/genética , Polimorfismo de Nucleótido Simple , Población Negra/genética , Aciltransferasas/genética , Fosfolipasas A2 Calcio-Independiente/genéticaRESUMEN
Despite the developments in cancer research over years, cancer is still one of the leading causes of death worldwide. In Brazil, the number of cancer cases for the several next years (2020-2022) is expected to increase up to 625,000. Thus, translational research has been vital to determine the potential risk, prognostic, and predictive biomarkers in cancer. Therefore, Barretos Cancer Hospital implemented a biobank (BB-BCH) in 2006, which is responsible for processing, storage, and provision of biological materials from cancer and non-cancer participants. Hence, this article aimed to describe BB-BCH's history, experiences, and outcomes and explore its impact on Brazilian translational oncology research scenario. BB-BCH has a multidisciplinary team who are responsible for guaranteeing the quality of all processes as recommended by international guidelines for biobanks. Furthermore, BB-BCH has ample equipment to ensure the quality of all material requested by researchers as genetic material (DNA and RNA) and/or entire biospecimens. From 2006 to 2019, BB-BCH contained 252,069 samples from 44,933 participants, the whole collection is represented by 15 different types of biospecimens collected from them. According to our data, the most collected and stored topography in men is head and neck (29%); in women is breast (28%); and in children is torso and limb (27%) samples. Finally, we supported national and international consortia and projects such as The Cancer Genome Atlas. BB-BCH is a vital knowledge source for scientific community, enabling the development of high-quality studies, with a wide variety of tumor categories and high national representativeness of Brazilian population.
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Investigación Biomédica , Neoplasias , Bancos de Muestras Biológicas , Biomarcadores , Instituciones Oncológicas , Niño , Femenino , Humanos , Masculino , ARN , Investigación Biomédica TraslacionalRESUMEN
Despite advances in diagnostic and therapeutic approaches for lung cancer, new therapies targeting metastasis by the specific regulation of cancer genes are needed. In this study, we screened a small library of epigenetic inhibitors in non-small-cell lung cancer (NSCLC) cell lines and evaluated 38 epigenetic targets for their potential role in metastatic NSCLC. The potential candidates were ranked by a streamlined approach using in silico and in vitro experiments based on publicly available databases and evaluated by real-time qPCR target gene expression, cell viability and invasion assays, and transcriptomic analysis. The survival rate of patients with lung adenocarcinoma is inversely correlated with the gene expression of eight epigenetic targets, and a systematic review of the literature confirmed that four of them have already been identified as targets for the treatment of NSCLC. Using nontoxic doses of the remaining inhibitors, KDM6B and PADI4 were identified as potential targets affecting the invasion and migration of metastatic lung cancer cell lines. Transcriptomic analysis of KDM6B and PADI4 treated cells showed altered expression of important genes related to the metastatic process. In conclusion, we showed that KDM6B and PADI4 are promising targets for inhibiting the metastasis of lung adenocarcinoma cancer cells.